MICROTUBULE-ASSOCIATED PROTEIN MICROTUBULE AFFINITY-REGULATING KINASE (P110(MARK)) - A NOVEL PROTEIN-KINASE THAT REGULATES TAU-MICROTUBULE INTERACTIONS AND DYNAMIC INSTABILITY BY PHOSPHORYLATION AT THE ALZHEIMER-SPECIFIC SITE SERINE-262
MICROTUBULE-ASSOCIATED PROTEIN MICROTUBULE AFFINITY-REGULATING KINASE (P110(MARK)) - A NOVEL PROTEIN-KINASE THAT REGULATES TAU-MICROTUBULE INTERACTIONS AND DYNAMIC INSTABILITY BY PHOSPHORYLATION AT THE ALZHEIMER-SPECIFIC SITE SERINE-262
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DOI：
10.1074/jbc.270.13.7679
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发表时间：
1995-03-31
影响因子：
4.8
通讯作者：
MANDELKOW, E
中科院分区：
文献类型：
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作者：
DREWES, G;TRINCZEK, B;MANDELKOW, E
微管相关蛋白tau的异常磷酸化是阿尔茨海默病神经元变性的病理特征之一。Ser-262在tau的微管结合区内的磷酸化是特别有意义的，因为到目前为止，它只在阿尔茨海默病中观察到(长谷川，M.，Morishima-Kawashima，M.，Takio，K，Suzuki，M.，Titani，K.和Ihara，Y.(1992)J.Biol)。化学。26,17047-17054)，因为这个位点的单独磷酸化大大降低了体外对微管的亲和力(Biernat，J.，Gustke，N.，Drewes，G.，Mandelkow，E.M.，和Mandelkow，E.(1993年)Neuron 11,153-163)。在这里，我们描述了一种从脑组织中分离纯化的蛋白质-丝氨酸激酶，在十二烷基硫酸钠凝胶上的表观分子质量为110 kDa。该激酶在重复结构域中特异性地磷酸化其KIGS或KCGS基序上的tau，而在该区域之外没有检测到显著的磷酸化。磷酸化主要发生在位于第一重复序列的Ser-262上。这在很大程度上取消了tau与微管的结合，使它们动态不稳定，与其他在重复结构域或附近磷酸化tau的蛋白激酶形成对比。这些数据表明，这种新的激酶在阿尔茨海默病中涉及微管相关蛋白/微管阵列重排及其病理性退化的细胞事件中发挥了作用。
Aberrant phosphorylation of the microtubule-associated protein tau is one of the pathological features of neuronal degeneration in Alzheimer's disease. The phosphorylation of Ser-262 within the microtubule binding region of tau is of particular interest because so far it is observed only in Alzheimer's disease (Hasegawa, M., Morishima-Kawashima, M., Takio, K,, Suzuki, M., Titani, K., and Ihara, Y. (1992) J. Biol. Chem. 26, 17047-17054) and because phosphorylation of this site alone dramatically reduces the affinity for microtubules in vitro (Biernat, J., Gustke, N., Drewes, G., Mandelkow, E. M., and Mandelkow, E. (1993) Neuron 11, 153-163). Here we describe the purification and characterization of a protein-serine kinase from brain tissue with an apparent molecular mass of 110 kDa on SDS gels. This kinase specifically phosphorylates tau on its KIGS or KCGS motifs in the repeat domain, whereas no significant phosphorylation outside this region was detected. Phosphorylation occurs mainly on Ser-262 located in the first repeat. This largely abolishes tau's binding to microtubules and makes them dynamically unstable, in contrast to other protein kinases that phosphorylate tau at or near the repeat domain. The data suggest a role for this novel kinase in cellular events involving rearrangement of the microtubule associated proteins/microtubule arrays and their pathological degeneration in Alzheimer's disease.